Undetected Respiratory Depression in People with Opioid Use Disorder.

BACKGROUND: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. METHODS: There were four groups of participants: 1) OUD plus COPD ('OUD-COPD', n = 13); 2) OUD without COPD ('OUD', n = 7); 3) opioid-naïve COPD patients ('COPD'n = 13); 4) healthy controls ('HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s RESULTS: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). CONCLUSIONS: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

Mobile telephone delivered contingency management for encouraging adherence to supervised methadone consumption: feasibility study for an RCT of clinical and cost-effectiveness (TIES).

BACKGROUND: Prescription methadone or buprenorphine enables people with opioid use disorder to stop heroin use safely while avoiding withdrawal. To ensure methadone is taken as prescribed and to prevent diversion onto the illicit market, people starting methadone take their daily dose under a pharmacist's supervision. Many patients miss their daily methadone dose risking withdrawal, craving for heroin and overdose due to loss of heroin tolerance. Contingency management (CM) can improve medication adherence, but remote delivery using technology may be resource-light and cost-effective. We developed an innovative way to deliver CM by mobile telephone. Software monitors patients' attendance and supervised methadone consumption through an internet self-login at the pharmacy and sends reinforcing text messages to patients' mobile telephones. A linked system sends medication adherence reports to prescribers and provides early warning alerts of missed doses. A pre-paid debit card system provides financial incentives. METHODS: A cluster randomised controlled trial design was used to test the feasibility of conducting a future trial of mobile telephone CM to encourage adherence to supervised methadone in community pharmacies. Each cluster (drug service/3 allied pharmacies) was randomly allocated to provide patient's presenting for a new episode of opiate agonist treatment (OAT) with either (a) mobile telephone text message CM, (b) mobile telephone text message reminders, or (c) no text messages. We assessed acceptability of the interventions, recruitment, and follow-up procedures. RESULTS: Four drug clinics were approached and three recruited. Thirty-three pharmacists were approached and 9 recruited. Over 3 months, 173 individuals were screened and 10 enrolled. Few patients presented for OAT and high numbers were excluded due to receiving buprenorphine or not attending participating pharmacies. There was 96% consistency in recording medication adherence by self-login vs. pharmacy records. In focus groups, CM participants were positive about using self-login, the text messages, and debit card. Prescribers found weekly reporting, time saving, and allowed closer monitoring of patients. Pharmacists reported that the tablet device was easy to host. CONCLUSION: Mobile telephone CM worked well, but a planned future trial will use modified eligibility criteria (existing OAT patients who regularly miss their methadone/buprenorphine doses) and increase the number of participating pharmacies. TRIAL REGISTRATION: The trial is retrospectively registered, ISRCTN 58958179 .

Microvascular changes of the retina in ankylosing spondylitis, and the association with cardiovascular disease - the eye for a heart study.

OBJECTIVE: Ankylosing spondylitis (AS) is associated with an increased risk of cardiovascular disease (CVD). Microvasculature changes can precede overt CVD, but have been studied poorly in AS. The retinal vasculature is easily accessible and changes are associated with CVD (e.g. arteriolar narrowing, venular widening, loss of tortuosity). This proof of concept study compared the retinal microvasculature of AS patients with healthy controls, and the influence of gender. METHODS: Cross-sectional case-control study comparing AS patients with healthy controls. Main inclusion criteria were: age 50-75 years, no diabetes mellitus and, for AS, fulfillment of the modified New York criteria. All subjects underwent fundus photography, analyzed with Singapore I Vessel Assessment software, and Optical Coherence Tomography Angiography (OCTA). Subjects were compared with generalized estimating equations (GEE). Multivariable analyses were adjusted for demographics and cardiovascular risk, and stratified for gender. RESULTS: Fifty-nine AS patients and 105 controls were included (50% women). Controls were significantly older than patients (68 versus 60, p<0.01), but did not differ in cardiovascular profile. Patients had a lower retinal arteriolar tortuosity (ß Ì¶-0.1, 95%CI [-0.2; -0.01], p = 0.02), and higher vessel density (ß 0.5, 95% CI [0.1; 0.9], p = 0.02). In addition, male AS patients showed a lower arteriovenular ratio compared to male controls (ß -0.03, p = 0.04, 95%CI [-0.05; -0.001]). There were no differences found between women with and without AS. CONCLUSION: This study detected several retinal microvascular changes, in AS patients compared to controls, which have been associated with CVD. Retinal imaging might be an interesting tool for future CVD screening.

Animal responses to herbage allowance: Forage intake and body weight gain of sheep grazing the Inner Mongolian steppe - Results of a six-year study.

An increasing human population and the growing demand for food of animal origin are leading to an intensification of sheep production and widespread overgrazing of the grassland steppe in Inner Mongolia. The aim of this study was to analyze the effect of herbage allowance (HA) on OM intake (OMI) and BW gain (BWG) of grazing sheep. In July to September 2005 to 2010, a grazing experiment was conducted in the Xilin River Basin using 15-mo-old female Mongolian fat-tailed sheep (31.5 kg BW [SE 0.2]). Six HA classes were tested on 4 experimental plots per HA class that were alternately used for grazing and haymaking each year (i.e., = 2 grazed plots per HA class and year). Mean HA ranged from 15.4 (SD 4.0) to 1.5 kg (SD 0.8) herbage DM/kg BW in HA class 1 to 6, respectively. In 6 sheep per plot (4 sheep in 2009 and 2010), OMI and BWG were determined. Titanium dioxide was used to determine fecal excretion, and digestibility of ingested OM was estimated from CP concentration in feces. Fecal grab samples were collected during 5 d each in July, August, and September. The animals were weighed monthly. Daily OMI of sheep ranged between 68 and 89 g/kg BW and was not affected by HA class ( = 0.373), so that total OMI per hectare was exponentially decreased with increasing HA (root mean square error [RMSE] ≤ 0.31 g/d; ≤ 0.003 for the slope estimates). The BWG of individual sheep increased with increasing HA in 2 of the 6 yr (RMSE 18.4 g/d; ≤ 0.175 for the positive slope estimates). Nevertheless, BWG per hectare strongly decreased with increasing HA (RMSE 0.25 g/d; ≤ 0.006 for the slope estimates). These data support the common practice of farmers to manage the grassland at low HA to allow for greater animal performance per unit of land area.

Treatment with Doxycycline of Generalized Annular Elastolytic Giant Cell Granuloma Associated with Borrelia burgdorferi Infection.

This is a case of generalized annular elastolytic giant cell granuloma (AEGCG) associated with borrelia infection and genes of p-30, p-31, p-39. A possible cross-mediated reaction from the T-cell type which might have induced the AEGCG is discussed from the concept of "heat-shock proteins (HSPs) and molecular mimicry".

The logistic curve as a tool to describe the daily ruminal pH pattern and its link with milk fatty acids.

Daily ruminal pH variation can be summarized by a cumulative logistic curve based on the amount of time below multiple pH points and characterized by 2 parameters (ß(0) and ß(1)). Moreover, rumen pH variation affects the rumen microbiome as well as the biohydrogenation pathways resulting in a modified secretion of milk fatty acids (FA). The aims of this study were to assess the shifts in milk FA due to rumen pH changes and to estimate the relationship between milk FA and the 2 parameters of the logistic curve. The data consisted of milk samples of 2 experiments. In experiment 1, 3 cows were subjected to 5 treatments in which the type and amount of concentrate were changed during 33 d: (1) control diet 1, (2) stepwise replacement of a standard concentrate (CONC) by a CONC rich in rapidly fermentable carbohydrates, (3) increase in the total amount of CONC, (4) treatment with a buffer solution, and (5) control diet 2. A 3×3 Latin square design with 3 cows was used in the second experiment. During the first 14 d of each period, the cows received a control diet with a standard CONC, whereas in the last 7 d the standard CONC was replaced step-by-step by a CONC rich in rapidly fermentable carbohydrates and the amount of CONC was increased. During each period, a different buffer treatment was added to the diet. Milk FA and pH reacted similarly in both experiments: decreasing proportions of iso FA and increasing proportions of odd-chain FA were observed. However, an abrupt change to a 76% CONC diet as for one cow of experiment 1 led to almost a 10-fold increase in C18:1 trans-10 (0.79 vs. 6.75 g/100g of FA). In experiment 2, the stepwise approach of adding CONC and the continuous supplementation of buffer led to minimal increases in C18:1 trans-10 and decreases in rumen pH compared with the diet with standard CONC only. Fatty acid proportions were influenced by the level of rumen pH (ß(1)) or the rumen pH variation (ß(0)), or both. High proportions of C18:1 trans-10 (above 4 g/100g of FA) occurred with low and largely fluctuating pH (low ß(1), low ß(0)), whereas situations with low, stable pH (low ß(1), great ß(0)) did not induce a shift toward the secondary biohydrogenation pathway. C18:1 trans-11 and C18:2 cis-9, trans-11 were only influenced by the pH variation and not by the average pH, whereas iso C14:0 and iso C16:0 FA were only dependent on the average pH and not influenced by diurnal pH variation. Overall, milk FA changes were related to pH changes; however, this relationship is not straightforward and needs further research.

Rotational and continuous grazing of sheep in the Inner Mongolian steppe of China.

The aim of this study was to compare the effects of rotational and continuous grazing on herbage mass (HM), organic matter digestibility (dOM) and intake (OMI) and live weight gain (LWG) of sheep grazing on the inner Mongolian steppe, China at a stocking rate of 4.5 sheep/ha during the growing season. In the years 2005 and 2006, four 2-ha plots were used of which two were divided into four 0.5 ha paddocks each for rotational grazing, where sheep were moved each 10 days to the next paddock. The dOM was estimated from faecal crude protein concentration and OMI by oral administration of titanium dioxide. Herbage mass was similar in both grazing systems and dOM and OMI were higher (p < 0.05) at continuous grazing than at rotational grazing, but LWG did not differ probably because of extra energy expenditure for grazing and walking in a larger area. The dOM and OMI decreased (p < 0.05) with progress of the growing season and differed between years. Since precipitation during the growing season in both years was lower than the 30 years average which was probably the reason that positive effects of non-grazing periods on herbage regrowth and quality at rotational grazing could not occur, further studies are required in years with average precipitations before a final evaluation of these grazing systems can be made. Moreover, it seems necessary to quantify energy expenditure for physical activity of animals in grazing studies.

Effects of perennial ryegrass cultivars on milk yield and nitrogen utilization in grazing dairy cows.

The effects of 4 diploid perennial ryegrass cultivars that differed in water-soluble carbohydrate (WSC) concentrations on milk yield and nitrogen (N) utilization in dairy cows were evaluated in a 2-yr grazing experiment. Twelve lactating dairy cows were assigned to 1 cultivar for a 2-wk period in a 4 x 4 Latin square design with 3 replicates. Each year, the experiment lasted 8 wk. Swards were in a vegetative stage throughout the experiment. Herbage constituents were determined, and DM intake was estimated with the n-alkane technique. Nitrogen utilization was calculated as N excreted in milk divided by N intake, assuming a zero N retention. Two cultivars had consistently higher WSC concentrations and slightly lower neutral detergent fiber concentrations than the other 2 cultivars. The ranking of the cultivars in chemical composition traits in both years was rather consistent. Cows grazing the cultivar with the lowest concentration of WSC had the lowest herbage DM intake, N intake, milk yield, and milk N yield in 2002, but with a similar difference in WSC concentration, no differences among cultivars were found in 2003. In both years, milk urea N concentration was slightly higher for cows grazing the cultivar with the lowest WSC concentration, although it was significant only in 2003. Nitrogen utilization (N milk:N intake, g/g) varied between 0.241 and 0.246 in 2002 and between 0.190 and 0.209 in 2003, and in both years there was no effect of cultivar. At relatively high N concentrations in grass and only small differences among cultivars in neutral detergent fiber concentrations, cultivars with an elevated WSC concentration did not increase N utilization in grazing dairy cows.

Effects of perennial ryegrass cultivars on intake, digestibility, and milk yield in dairy cows.

The effects of 8 diploid perennial ryegrass (Lolium perenne L.) cultivars on dry matter (DM) intake, DM digestibility, and milk yield (MY) of dairy cows were evaluated in the summer of 2000 and 2001. Each summer, herbage was harvested daily and stall-fed to 12 dairy cows during six 2-wk periods. Six cultivars were fed in 3 periods (1, 3, and 5) according to a double 3 x 3 Latin square design. In the other periods (2, 4, and 6), 2 cultivars were fed in a repeated measurement design. Herbage mass and leaf blades in the sward canopy varied among cultivars, but differences were not consistent between years. The largest differences in herbage composition were found in water-soluble carbohydrate content, followed by crude protein content. only small differences were found in the neutral detergent fiber (NDF) content. A higher water-soluble carbohydrate content was found in 2 cultivars in both years, whereas ranking of cultivars in crude protein and NDF content was not consistent with years. Dry matter intake and MY were not affected by cultivar. In both years, DM digestiblity was high (>77%), with very small differences among cultivars in 2000 (<0.5%) and larger differences in 2001 (up to 4%). This was associated with a delayed heading date in 2001, resulting in larger differences in leaf blades and NDF content among cultivars. It may be concluded that the 8 cultivars used in our experiments do not provide grass breeders with encouraging evidence to include selection criteria for an increased DM intake, DM digestibility, and MY in their grass breeding schemes.

Comparison of techniques for estimating herbage intake of grazing dairy cows.

For estimating herbage intake during grazing, the traditional sward cutting technique was compared in grazing experiments in 2002 and 2003 with the recently developed n-alkanes technique and with the net energy method. The first method estimates herbage intake by the difference between the herbage mass before and after grazing and the regrowth between the 2 points in time. The second technique estimates herbage intake by the ratio of a dosed even-chain synthetic n-alkane (C32) and a naturally occurring odd-chain n-alkane (C31 or C33) in the herbage and feces. The third technique calculated the intake from the animal's energy requirements for milk production and maintenance. The sward cutting technique estimated herbage intake with the highest coefficient of variation and had different results in the 2 experimental years. The n-alkanes method yielded less variable results, whereas the net energy method gave the least variable results. In 2002, the estimates of the alkane ratio C32:C33 were best related with estimations of the net energy method. In 2003, the estimates of the alkane ratio C32:C31 were best related. The estimate based on the alkane ratio C32:C33 had a lower coefficient of variation than the one based on the alkane ratio C32:C31. Therefore, the C32:C33 alkane method was considered to be a better direct estimator for herbage intake by grazing lactating dairy cows.

Intake regulation and grazing behavior of dairy cows under continuous stocking.

This experiment aimed at studying the behavioral strategies grazing dairy cows use to satisfy their nutritional needs as the day progresses and the possible role of rumen fill in controlling these behavioral strategies. The day was divided into 3 main periods (0600 to 1200 h, 1200 to 1800 h, and 1800 to 2400 h), where the 3 main grazing bouts (dawn, afternoon, and dusk) of dairy cows usually occur. Four late lactating rumen-cannulated dairy cows were used in a repeated measures design; grazing bout was the within-subjects factor. Cows had access to a 1-ha grass sward under a continuous stocking system. To estimate dry matter intake, bite rate, bite mass (BM), and intake rate at the 3 grazing bouts, cows were rumen-evacuated at 0600, 1200, 1800, and 2330 h, and the jaw recorders were fitted to the cows between these time points. Time spent eating by dairy cows at the dusk grazing bout was much longer than that at the other 2 grazing bouts and composed about 40% of the daily total eating time. Total grazing jaw movement (TGJM) rate was constant during the day at around 75/min. Bite rate, BM, and, hence, intake rate increased, but chewing rate decreased as the day progressed. The increase in BM was mainly due to the increase in dry matter content of the grass at dusk rather than increased bite dimensions. Therefore, it could be concluded that the main behavioral strategies dairy cows use to satisfy their nutritional needs under continuous stocking include manipulating their eating time, biting rate, and chewing rate, with little control over TGJM rate and BM. Dairy cows interrupted the first 2 grazing bouts (dawn and afternoon) long before reaching their maximal rumen capacity, indicating that rumen fill is less likely to play a significant role in signaling the termination of these 2 grazing bouts. However, rumen pool sizes were always maximal at the time when the dusk grazing bout ceased, indicating that rumen fill is more likely to play a major role in signaling the termination of the dusk grazing bout.

Triggering of ovulation using a gonadotrophin-releasing hormone agonist does not prevent ovarian hyperstimulation syndrome.

A total of 24 women with primary or secondary infertility due to oligo- or anovulation, were treated with human menopausal gonadotrophin (HMG). In 48 cycles, we used a gonadotrophin-releasing hormone agonist (GnRHa) nasal spray (buserelin) to induce a pre-ovulatory endogenous luteinizing hormone (LH) surge. In 44 cycles, there was a rapid rise of the serum LH concentration within 8 h from the first administration of GnRHa. One patient with pituitary hypogonadotrophic amenorrhoea showed a weak or no response in four treatment cycles. Conception occurred in 10 cycles (pregnancy/cycle (P/C) index = 22.7%), four of which ended in a spontaneous abortion and six of which are ongoing pregnancies. In 27 cycles, there was an increased risk for ovarian hyperstimulation syndrome (OHSS), defined as more than three follicles > or = 18 mm in diameter and/or serum oestradiol > 1200 pg/ml. Three of these treatment cycles gave rise to the development of moderate OHSS in the absence of exogenously administered human chorionic gonadotrophin, two being conception cycles.

The intercostal-to-phrenic-inhibitory reflex (IPIR) in normal and intra-uterine growth-retarded (IUGR) human fetuses from 26 to 40 weeks of gestation.

The existence of an IPIR in the healthy fetus between 37 and 40 weeks of gestation has already been demonstrated: compression of the fetal thoracic wall during an epoch of fetal breathing movements (FBM) consistently caused a fetal apnea (> or = 4 s). The apnea durations were similar in fetal behavioural states 1F and 2F, with a wide inter- and intrafetal variability. We therefore hypothesized that the duration of the IPIR-apnea would increase during gestation and would be increased in IUGR-fetuses as compared to healthy fetuses of the same age. Twenty-six healthy fetuses between 28 and 40 weeks (mean 34.3 weeks) and 14 IUGR-fetuses between 26 and 38 weeks (mean 33.5 weeks) were studied. If FBM were present, the caudolateral part of the fetal thoracic wall was shortly compressed manually and the duration of the resulting apnea was measured. In a random order a sham-compression was also carried out on the fetal head. In normal fetuses 21/28 real compressions were followed by an apnea in 1F, while this was only the case in 3/21 sham-compressions (P < 10(-4)). For 2F these results were 47/57 and 7/51, respectively (P < 10(-4)). In IUGR-fetuses 43/51 real compressions (1F and 2F together) and 7/46 sham-procedures provoked an apnea (P < 10(-4)). These results prove the existence of the IPIR in normal and IUGR-fetuses. The mean (+/- S.D.) duration of apnea in the IUGR-fetuses was 15.8 s (+/- 4.0) (range 4-80 s) and 15.2 s (+/- 4.3) (range 4-106 s) in the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)

The intercostal-to-phrenic inhibitory reflex in the human fetus near term.

Human fetal breathing movements (FBM) differ from neonatal breathing in that they are predominantly paradoxical and are not present all the time. Respiratory pauses are common in the fetus while prolonged apneas are life-threatening in the neonate. In the latter they occur during state 2 (active sleep) when paradoxical breathing is more frequent. Then the inward movement of the thoracic wall causes spreading of the caudal ribs which may elicit an intercostal-to-phrenic inhibitory reflex (IPIR) leading to apnea. This is not the case in state 1 (quiet sleep). In the fetus similar sleep states, state 2F and 1F respectively, have been identified and we investigated if the IPIR is already present before birth and if so, if the response is different between 1F and 2F. In 21 healthy fetuses between 37 and 40 weeks, two real time scanners and a cardiotocograph were used to asses the fetal behavioural state. If FBM were present, the caudo-lateral part of the fetal thoracic wall was shortly compressed manually and the period that FBM ceased measured. During the same epoch moments of sham-stimulation, i.e. control periods without actual compression were also carried out. In 15 out of 16 fetuses with FBM in 1F, and in 19 out of 19 fetuses in 2F, compressions were immediately followed by an apnea. In contrast, moments of sham-stimulation never induced apnea, indicating that the IPIR is indeed present in both behavioural states.(ABSTRACT TRUNCATED AT 250 WORDS)